Clinical Overview of Combination Therapy with Sitagliptin ... · Sitagliptin Consistently and Significantly Lowers A1C with Once-Daily Dosing in Monotherapy 7.2 7.6 8.0 8.4 ... Raz

Clinical Overview of Combination Therapy with Sitagliptin and Metformin

1

Contents

Pathophysiology of type 2 diabetes and mechanism of action of sitagliptin

Clinical data overview of sitagliptin:Monotherapy (PN021, 023, A201)

Complexities of getting patients to goal: a rationale for earlier combination therapy

Mechanism of action of the co-administration of sitagliptin plus metformin

Clinical data overview of combination therapy with sitagliptin and metformin 8

Major Pathophysiologic Defects in Type 2 Diabetes

Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.

Hepatic glucoseoutput

Insulin resistance

Glucose uptake

Glucagon(α cell)

Insulin(β cell)

LiverLiver

Hyperglycaemia

Islet-Cell Dysfunction

MuscleMuscleAdipose Adipose tissuetissue

PancreasPancreas

4

Mechanism of Action of Sitagliptin

Release ofactive incretins

GLP-1 & GIP Blood glucose in fasting and postprandial

states

Ingestion of food

Glucagon(GLP-1)

Hepatic glucose

production

GI tract

DPP-4 enzyme

InactiveGLP-1

XJANUVIA(DPP-4

inhibitor)

Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels in response to a meal.

Insulin(GLP-1and

GIP)

Glucosedependent

Glucose-dependent

Pancreas

InactiveGIP

GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

Concentrations of the active intact hormones are increased by JANUVIA™ (sitagliptin phosphate), thereby increasing and prolonging the actions of these hormones.

Beta cellsAlpha cells

Glucose uptake by peripheral

tissue

Sitagliptin - Overview

Provides potent and highly selective inhibition of the DPP-4 enzyme

Fully reversible and competitive inhibitor

DPP-4 inhibitor in development for the treatment of patients with type 2 diabetes, approved by the FDA on October 17 2006, and approved in EU on March 26 2007

Approved in Korea on September 21 2007

N

ONH2

NN

CF3

F

F

F

N

Pharmacokinetics of Sitagliptin Supports Once-Daily Dosing

With once-daily administration, trough (at 24 hrs) DPP-4 inhibition is ~ 80%> 80% inhibition provides full enhancement of active incretin levels

No effect of food on pharmacokinetics Well absorbed following oral dosing

Tmax app 2 hours, t1/2 app 12.4 hours at 100 mg doseLow protein binding, app 38% Primarily renal excretion as parent drug

Approximately 80% of a dose recovered as intact drug in urine

No clinically important drug-drug interactionsNo meaningful P450 system inhibition or activation

Single-Dose OGTT Study

One Dose of Sitagliptin Inhibited Plasma DPP-4 Activity

Hours post-dose

~80%

~50%

Trough DPP-4inhibition

Inhi

bitio

n of

pla

sma

DPP

-4ac

tivity

from

bas

elin

e (%

)

0 1 2 4 8 12 16 20 24–10

0

40

50

60

80

100

90

70

30

20

10

6 10 14 18 22 26

OGTT

Sitagliptin 25 mg (n=56)Sitagliptin 200 mg (n=56)Placebo (n=56)

OGTT=oral glucose tolerance test; AUC=area under the curveHerman et al. J Clin Endocrinol Metab, November 2006, 91(11):4612–4619. PN005

OGTT 24 hrs (n=19)

Active GLP-1

A Single Dose of Sitagliptin Increased Active GLP-1 and GIP Over 24 Hours

0

5

10

15

20

25

30

35

40

0 2 4 6 24 26 28

GLP

-1 (p

g/m

L)

Hours Postdose

OGTT 2 hrs (n=55)

Crossover study in patients with T2DM Placebo

Sitagliptin 25 mg

Sitagliptin 200 mg

2-fold increase in active GLP-1

p< 0.001 vs placebo

Active GIP

0102030405060708090

0 2 4 6 24 26 28Hours Postdose

GIP

(pg/

mL)

OGTT 24 hrs (n=19)

OGTT 2 hrs (n=55)

2-fold increase in active GIP

p< 0.001 vs placebo

Herman et al. J Clin Endocrinol Metab, November 2006, 91(11):4612–4619. PN005

A Single Dose of Sitagliptin Increased Insulin, Decreased Glucagon, and Reduced Glycemic Excursion After a glucose Load

Placebo

Sitagliptin 25 mg

Sitagliptin 200 mg

0

10

20

30

40

0 1 2 3 4

mcI

U/m

L

50

55

60

65

70

75

0 1 2 3 4Time (hours)

pg/m

L

Glucose load

Drug Dose 22%

~12%

Insulin

Glucagon

p<0.05 for both dose comparisons to placebo for AUC

Crossover Study in Patients with T2DM

p<0.05 for both dose comparisons to placebo for AUC Glucose load

Drug Dose

120

160

200

240

280

320

0 1 2 3 4 5 6Time (hours)

Glucose

~26%

p<0.001 for both dose comparisons to placebo for AUC

Herman et al. J Clin Endocrinol Metab, November 2006, 91(11):4612–4619. PN005

Contents


Clinical data overview of sitagliptin:Monotherapy (PN021, PN023, A201, and PN040)




11

Sitagliptin Consistently and Significantly Lowers A1C with Once-Daily Dosing in Monotherapy

7.2

7.6

8.0

8.4

Placebo (n=244)

Sitagliptin 100 mg (n=229)

Time (weeks)

24-week Study

0 5 10 15 20 25

-0.79%(p<0.001)

*between group difference in LS means

Japanese Study

-1.05%(p<0.001)

Placebo (n=75)


Time (weeks)

0 4 8 12

A1C

(%)

7.6

8.0

8.4

7.2

6.8

Δchange vsplacebo*

18-week Study

Placebo (n=74)


Time (weeks)

0 6 12 18

A1C

(%)

7.2

7.6

8.0

8.4

-0.6%(p<0.001)

A1C

(%)

=

Raz I et al. Diabetologia 2006;49:2564-2571 ; PN023; Aschner P et al. Diabetes Care 2006;29:2638-2643 ; PN021; Nonaka K et al; A201. Abstracts presented at: ADA 2006

Sitagliptin Provides Significant and Progressively Greater Reductions in A1C with Progressively Higher Baseline A1C

Reductions are placebo-subtracted

Baseline A1c (%)

Mean (%)

Red

uctio

n in

A1c

(%)

Inclusion Criteria: 7%–10%

Red

uctio

n in

A1c

(%)

<8% 8–9% >9%

7.37 8.40 9.48

<8% 8–9% >9%

7.39 8.36 9.58

N=96

N=70

N=27

N=130

N=62

N=37

18-week Study

-0.44-0.61

-1.2-1.8-1.6-1.4-1.2-1.0-0.8-0.6-0.4-0.20.0

24-week Study

-0.57

-0.8

-1.52-1.8-1.6-1.4-1.2-1.0-0.8-0.6-0.4-0.20.0

N=130

N=62

N=37


Sitagliptin Once Daily Significantly Improves Both Fasting and Post-meal Glucose In Monotherapy

* LS mean difference from placebo after 24 weeks Aschner P et al, PN021. Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC

Fasting Glucose

Pla

sma

Glu

cose

mg/

dL

Time (weeks)

0 5 10 15 20 25144

153

162

171

180

189

Placebo (n=247)Sitagliptin 100 mg (n=234)

Δ FPG* = –17.1 mg/dL (p<0.001)

Time (minutes)

Post-meal Glucose

Pla

sma

Glu

cose

mg/

dL

Δ in 2-hr PPG* = –46.7 mg/dL (p<0.001)

0 60 120 0 60 120

144

180

216

252

288

Placebo (N=204) Sitagliptin (n=201)

Baseline24 weeks

Baseline24 weeks

Sitagliptin Improved Markers of Beta-Cell Function In 24-Week Monotherapy Study

Proinsulin/insulin ratio

p< 0.001*

*P value for change from baseline compared to placebo

Hatched = BaselineSolid = Week 24∆ from baseline vs pbo = 0.078

(95% CI -0.114, -0.023)

Placebo Sitagliptin 100 mg

Rat

io (p

mol

/L /

pmol

/L)

HOMA-β

p< 0.001*

∆ from baseline vs pbo = 13.2 (95% CI 3.9, 21.9)

Placebo Sitagliptin 100 mg0.3

0.35

0.4

0.45

0.5

0.55

30

35

40

45

50

55

60

65

70

75

80


Sitagliptin Monotherapyin Asian Patients (PN040)

A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of Sitagliptin

Monotherapy in Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control

Study Design

AHA = antihyperglycemic agent; FPG = fasting plasma glucose; R = randomization; T2DM = type 2 diabetes mellitus.

Single-Blind Placebo

Sitagliptin100 mg

Pbo

Screening Period

• Patients with T2DM

• ≥18 years of age

• Not on AHA A1C ≥7.5% and ≤11%

• On AHA A1C ≥7% and ≤10%

Double-Blind Treatment Period

Diet/ExerciseRun-in Period

R

Single-Blind

Placebo Run-in

A1C ≥7.5 and ≤11% FPG ≥130 mg/dL and ≤ 280 mg/dL

Visit 1ScreeWk –9

ning Visit 2Run-in

Start Wk –8

Visit 4Wk –2

Start SB

Visit 5Day 1

Randomization

Visit 8Wk 18

Visit 3Wk –5

Visit 6Wk 6

Visit 7Wk 12

Baseline Glycemic and Disease Characteristics Balanced Between Groups

Age (yrs)

BMI (mean, kg/m2 )

A1C (%)

FPG (mg/dl)

Fasting insulin (μIU/mL )

Duration of Diabetes Mellitus ( yrs)

HOMA Beta (%)

Characteristic

50.9 ± 9.3

24.9 ± 3.4

8.75 ± 1.06

181.6 ± 42.5

10.0 ± 8.4

1.9 ±1.6

32.0

Placebo

(n=178)Sitagliptin

(n=352)

50.9 ± 9.3

25.1 ± 3.4

8.74 ± 1.01

189.0 ±

44.0

9.7 ± 8.2

2.1 ± 1.7

33.0

Change from Baseline in HbA1c Full-Analysis-Set Population

0 6 12 18

Week

-0.8

-0.6

-0.4

-0.2

0.0

0.2

LS M

ean

Cha

nge

from

Bas

elin

e

0.4

Sitagliptin 100 mg Placebo

-1.03%

Change from Baseline Per Country

Country GroupPlacebo

Subtracted % A1c change

Placebo Subtracted

mg/dL FPG

Placebo Subtracted

mg/dL PPG

Sita (n=119)India

Plbo (n=59)

ChinaPlbo (n=79)

Plbo (n=31)Korea

-38.8 -49.8

Sita (n=158)

-1.36

-0.68

-1.37

-18.2 -49.9

Sita (n=62)-54.5 -90.6

HbA1c Reduction in Korean Diabetes Patients

GroupPlacebo

Subtractedmg/dL FPG

Placebo Subtractedmg/dL PPG

Sita (n=62)Plbo (n=31)

-54.5 -90.6

Mea

n ch

ange

of A

1Cfr

om b

asel

ine(

%)

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

12wks 18wks

Sitagliptin vs. placebo = -1.37%

-10wks 6wks

Sitagliptin

Placebo

Summary(PN040: Sitagliptin Monotherapy in Asian patients)

Sitagliptin demonstrated strong glycemic efficacy compared to placebo, as measured by HbA1c, FPG and PPG

Sitagliptin was overall well tolerated

No hypoglycemia

For adverse experiences within GI system organ class, a higher incidence was observed with Sitagliptin

Contents






ADA and IDF Guidelines:Treatment Goals for HbA1c, FPG, and PPG

ParameterNormalLevel

ADA Goal

IDF Goal

FPG, mg/dl(mmol/L)

<110(<6.1)

90–130(5.0–7.2)

<100(<5.5)

PPG, mg/dl(mmol/L)

<140(<7.8)

<180(<10.0)

<140(<7.8)

HbA1c 4%–6% <7%* <6.5%

*Reference to a nondiabetic range of 4.0% to 6.0% using a DCCT-based assay.ADA=American Diabetes Association; IDF=International Diabetes Federation.American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41; International Diabetes Federation. 2007:1–32.Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.

9

Societies Recommend Earlier Intervention to Help Attain Glycaemic Control

2006 Consensus statement from the ADA and EASD“Our consensus is that an HbA1c of ≥7 should serve as a call to action to initiate or change therapy…”

“If lifestyle intervention and maximal tolerated dose of metformin fail to achieve or sustain glycaemic goals, another medication should be added within 2–3 months of the initiation of therapy or at any time when HbA1c goal is not achieved”

2005 Global Guideline by IDF“Begin with metformin unless evidence or risk of renal impairment, titrating the dose over early weeks to minimise discontinuation due to gastro-intestinal intolerance”

“Step up doses, and add other glucose-lowering drugs, at frequent intervals until blood glucose control is at target levels”

EASD=European Association for the Study of Diabetes.Nathan DM et al. Diabetologia. 2006;49:1711–1721; International Diabetes Federation. 2005:1–79.

10

HbA1c Levels Above ADA/EASD Target Goals HaveNot Triggered Timely Therapy Modificationsa

aUS Physicians; 1994–2002bMean number of months that elapsed until a new or additional treatment was started. cMonotherapy switched to another agent or additional agent added.Brown JB et al. Diabetes Care. 2004;27:1535–1540; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41; Nathan DM et al. Diabetologia. 2006 Aug;49(8):1711–21.

First HbA1c on Treatment

Best HbA1c on Treatment

Last HbA1c before Switch or Additionc

ADA goal

EASD goal

27b

months

35b

months

8.2

7.7

8.8

7.6

7.1

9.1

6

7

8

9

10

Metformin monotherapy (n=513 episodes)

Sulfonylurea monotherapy (n=3394 episodes)

0

HbA

1c, %

ADA=American Diabetes Association.EASD=European Association for the Study of Diabetes.

11

Traditional Type 2 Diabetes Management: A “Treat-to-Fail Approach”

OAD=oral anti-hyperglycaemic drug.Adapted from Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7(10):625–631.Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.

7

8

6

9

10

OAD monotherapy

Diet andexercise

OAD combination

OAD up-titration

OAD plus multiple daily

insulininjections

OAD plus basal insulin

HbA

1c, %

Mean HbA1cof patients

Duration of Diabetes

Published Conceptual Approach

Time

12

Less than 50% of Adults With Type 2Diabetes Have Achieved HbA1cGoals

NHANES=National Health and Nutrition Examination Survey of a US population.Adapted from Saydah SH et al. JAMA. 2004;291:335–342.

HbA1c level<7%

Blood pressure <130/80 mmHg

Total cholesterol<200 mg/dl

Achieved all 3 treatment goals

CV Risk Factors

44.3

29.033.9

5.2

37.0 35.8

48.2

7.3

0

10

20

30

40

50

60

Adu

lts, %

NHANES III (1988–1994) (n=1204)NHANES 1999–2000 (n=370)

US Population

13

UKPDS: Improving HbA1c Control Reduced Diabetes-Related Complications

UKPDF=United Kingdom Prospective Diabetes Study. Data adjusted for age, sex, and ethnic group, expressed for white men aged 50–54 years at diagnosis and with mean duration of diabetes of 10 years. Stratton IM et al. UKPDS 35. BMJ 2000;321:405–412.

EVERY 1% reduction in HbA1c

REDUCED RISK(P<0.0001)

1%

Diabetes-related deaths

Myocardial infarctions

Microvascular complications

Amputations or deaths from peripheral

vascular disorders

21%

14%

37%

43%

Relative RiskN=3642

14

Major Targeted Sites of Oral Drug Classes

Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303; Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.

DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.

Glucose Glucose absorptionabsorption

Hepatic glucoseHepatic glucoseoverproductionoverproduction

Impaired insulinImpaired insulinsecretionsecretion

InsulinInsulinresistanceresistance

Pancreas

↓Glucose level

Muscle and fatLiver

BiguanidesTZDs Biguanides

Sulfonylureas

Meglitinides

TZDs

α-Glucosidase inhibitors

Gut

DPP-4 inhibitors

DPP-4 inhibitors

Biguanides

15

Mechanisms of Action of Major Oral Monotherapies Are Unable to Address the 3 Core Defects in Type 2 Diabetes

Oral Monotherapies

SUs Meglitinides TZDs Metforminα-Glucosidase

Inhibitors

Lowers hepatic glucose production

DPP-4 Inhibitors

Improves insulin secretion

Improves insulin resistance

SUs=sulfonylureas; TZD=thiazolidinediones; DPP-4=dipeptidyl peptidase 4.Inzucchi SE. JAMA 2002;287:360–372; Gallwitz B. Minerva Endocrinol. 2006;31:133–147; Nathan DM et al. Diabetologia. 2006;49:1711–1721.

Mec

hani

sms

of A

ctio

n

16

7

6

9

8

10

Mean HbA1cof patients

HbA

1c, %

Duration of Diabetes

OAD monotherapy

Diet andexercise

OAD combination

OAD up-titration

OAD plus multiple daily

insulininjections

OAD plus basal insulin

Published Conceptual Approach

Earlier Use of Combination Therapy May Improve Treating to Target Compared With Conventional Therapy

Time

18OAD=oral anti-hyperglycaemic drug.Adapted from Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7(10):625–631.Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.

Summary—Complexities of Getting Patients to Goal:A Rationale for Earlier Combination Therapy

Percentage of patients with type 2 diabetes getting to glycaemic goal is far from optimalCurrent conventional treatment paradigm has been characterised by ‘treatment to failure’ rather than ‘treatment to success’

Physicians see adverse events and adherence as the main barriersto earlier use of current combination therapy regimens

Revised/proactive treatment paradigm for type 2 diabetes, involving earlier use of combination therapy, is urgently needed to be more effective in reaching and maintaining HbA1c goals

Saydah SH et al. JAMA. 2004;291:335–342; Brown JB et al. Diabetes Care. 2004;27:1535–1540; Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355; Campbell IW. Br J Cardiol. 2000;7:625–631; Grant RW, et al. Diabetes Care. 2003;26:1408–1412; Dailey G et al. Clin Ther. 2001;23:1311–1320. 19

Contents





Clinical data overview of combination therapy with sitagliptin and metformin (PN024) 8

The Combination of Sitagliptin and Metformin Addresses the 3 Core Defects of Type 2 Diabetes

in a Complementary Manner

Sitagliptin improvesmarkers of β-cell function andincreases insulin synthesis and release

Sitagliptin indirectly reducesHGO through suppression ofglucagon from α cells

Metformin significantlydecreases HGO by directly

targeting the liver to decreasegluconeogenesis and

glycogenolysis

Metformin acts as aninsulin sensitiser(liver>muscle/fat)

β-Cell Dysfunction

Insulin Resistance

Hepatic Glucose OverproductionHepatic Glucose Overproduction

HGO=hepatic glucose overproduction.Aschner P et al. Diabetes Care. 2006;29:2632–2637; Abbasi F et al. Diabetes Care. 1998;21:1301–1305; Inzucchi SE. JAMA 2002;287:360–372; Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33; Zhou G et al. J Clin Invest. 2001;108:1167–1174.

22

Contents





Clinical data overview of combination therapy with sitagliptin and metformin (PN024) 8

HbA1c With Sitagliptin or Glipizide as Add-on Combination With Metformin: Comparable Efficacy

LSM change from baseline (for both groups): –0.7%

Achieved primary hypothesis of non-

inferiority to sulfonylurea

Sulfonylureaa + metformin (n=411)Sitagliptinb + metformin (n=382)

HbA

1c, %

±SE

Weeks

6.2

6.4

6.6

6.8

7.0

7.2

7.4

7.6

7.8

0 6 12 18 24 30 38 46 52

8.0

8.2

aSpecifically glipizide ≤20 mg/day;bSitagliptin 100 mg/day with metformin (≥1500 mg/day).

Per-protocol population; LSM=least squares mean.SE=standard error.

27

Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes ObesMetab. 2007;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.

Greater Reductions in HbA1c Associated With Higher Baseline HbA1c – 52-Week Post Hoc Analysis

n=117

Baseline HbA1c Category

Mea

n C

hang

e Fr

om B

asel

ine

in H

bA1c

, %

<7% ≥7 to <8% ≥8 to <9% ≥9%

− 0.1

− 0.6

−1.1

−1.8

− 0.3

−0.5

−1.1

−1.7

−2.0

−1.8

−1.6

−1.4

−1.2

−1.0

−0.8

−0.6

−0.4

−0.20.0

Sitagliptinb plus metformin

Sulfonylureaa plus metformin

n=33 n=21n=82 n=82n=179 n=167n=112

aSpecifically glipizide ≤20 mg/day.bSitagliptin 100 mg/day with metformin (≥1500 mg/day);

Per-protocol population. Add-on sitagliptin with metformin vs sulfonylurea

with metformin study.28


Sitagliptin With Metformin Provided Weight Reduction (vs Weight Gain) and a Much Lower Incidence of Hypoglycaemia

aSpecifically glipizide ≤20 mg/day; bSitagliptin (100 mg/day) with metformin (≥1500 mg/day);

cAll-patients-as-treated population.Least squares mean between-group difference at week 52 (95% CI):

change in body weight = –2.5 kg [–3.1, –2.0] (P<0.001);Least squares mean change from baseline at week 52:

glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<0.001).Add-on sitagliptin with metformin vs sulfonylurea

with metformin study.

Δ between groups = –2.5 kg

Least squares mean change over timec

Bod

y W

eigh

t, kg

±SE

Sulfonylureaa plus metformin (n=416)

Sitagliptinb plus metformin (n=389)

−3

−2

−1

0

1

2

3

Weeks0 12 24 38 52

Hypoglycaemiac

P<0.001

32%

5%

0

10

20

30

40

50

Week 52Pa

tient

s W

ith ≥

1 Ep

isod

e, %

P<0.001

Sulfonylureaa plus metformin (n=584)

Sitagliptinb plus metformin (n=588)

29


Summary: Sitagliptin or Glipizide as Add-on Combination With Metformin

Efficacy profileComparable efficacy in lowering HbA1c

Both provided greater HbA1c reductions in patients with the highest baseline HbA1c

Safety profileBoth were generally well tolerated

Adverse event profiles (ie, serious and GI-related adverse events, those leading to discontinuation) were similar, with the exception of hypoglycaemia– Significantly lower incidence of hypoglycaemic episodes associated with

sitagliptin with metformin

Body weight significantly decreased for sitagliptin with metformin, but increased for glipizide with metformin

Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205.30

Summary

Insulin resistance, β-cell dysfunction, and elevated hepatic glucose production are the 3 core pathophysiologies of type 2 diabetesIncretins positively affect glucose homeostasis by physiologically helping to regulate

Insulin secretion from β cells in a glucose-dependent mannerGlucagon secretion in a glucose-dependent manner

Getting patients to goal may be enhanced by targeting all 3 core defects and hyperglycaemia in the fasting and post-prandial states

Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781; Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254; Drucker DJ. Diabetes Care. 2003;26:2929–2940; Nauck MA et al. Diabetologia. 1993;36:741–744; Monnier L et al. Diabetes Care. 2003;26:881–885; American Diabetes Association. Diabetes Care. 2007;30(Suppl 1):S4–S41; International Diabetes Federation. 2008:1–32.

41

Summary (Continued)

Sitagliptin and metformin have complementary mechanisms of action that address all 3 core defects of type 2 diabetes Sitagliptin as add-on combination with metformin provided HbA1c reductions comparable to adding an SU

With less hypoglycemiaWith weight loss

Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205;; Goldstein BJ et al. Diabetes Care. 2007;30:1979–1987; Hermansen K et al. Diabetes Obes Metab. 2007;9:733–745. 42

Thank You!

Clinical Overview of Combination Therapy with Sitagliptin ... · Sitagliptin Consistently and Significantly Lowers A1C with Once-Daily Dosing in Monotherapy 7.2 7.6 8.0 8.4 ... Raz

Documents